JP2004224802A - Antibacterial agent - Google Patents
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Abstract
Description
この発明は、抗菌剤に関するものである。さらに詳しくは、この発明は、優れた活性を有するフラノナフトキノン誘導体を有効成分とする新規な抗菌剤に関するものである。 The present invention relates to an antibacterial agent. More specifically, the present invention relates to a novel antibacterial agent containing a furanonaphthoquinone derivative having excellent activity as an active ingredient.
ＲＮＡウイルスの感染によって起こる疾患には、日本脳炎、デング熱、麻疹、流行性耳下腺炎、風疹、インフルエンザ、Ａ型肝炎、Ｃ型肝炎、黄熱病、出血熱、髄膜炎、小児性下痢症、狂犬病、エボラ出血熱、ラッサ熱、ポリオ、セントルイス脳炎、成人Ｔ細胞白血病、エイズ等があり、さらにＲＮＡウイルス感染が原因と推定されている難治性疾患としては、慢性関節リウマチ、全身性エリテマトーデス、多発性硬化症、亜急性硬化性全脳炎、アルツハイマー病、潰瘍性大腸炎、クローン病、川崎病、糖尿病等があることが知られている。しかしながら、現状においては、ＲＮＡウイルス感染病に対して有効な化学治療薬はほとんど見出されていない。 Diseases caused by RNA virus infection include Japanese encephalitis, dengue fever, measles, mumps, rubella, influenza, hepatitis A, hepatitis C, yellow fever, hemorrhagic fever, meningitis, pediatric diarrhea , Rabies, Ebola hemorrhagic fever, Lassa fever, polio, St. Louis encephalitis, adult T-cell leukemia, AIDS, and the like. Intractable diseases that are presumed to be caused by RNA virus infection include rheumatoid arthritis, systemic lupus erythematosus, and multiple It is known that there are sclerosis, subacute sclerosing panencephalitis, Alzheimer's disease, ulcerative colitis, Crohn's disease, Kawasaki disease, diabetes and the like. However, at present, few chemotherapeutic agents effective against RNA virus infectious diseases have been found.
実際にも、たとえば日本脳炎、インフルエンザ、麻疹、風疹、流行性耳下腺炎、ポリオ等の関連ウイルスが特定されているものについては、不活化ワクチンや生ワクチンを用いる予防治療がなされるのみであり（狂犬病は血清療法）、発症した場合の治療効果は低いのが実情である。また、非特異的な生体内抵抗物質であるインターフェロン（ＩＦＮ）が現在最も有効な抗ウイルス剤として知られているが、このものは宿主細胞に対する毒性があり、発熱、全身倦怠感、頭痛、食欲不振、白血球血小板減少、中枢神経障害等の副作用が大きいという問題がある。 In fact, for those related viruses such as Japanese encephalitis, influenza, measles, rubella, mumps, polio, etc., prophylactic treatment using inactivated vaccines or live vaccines is only performed. Yes (serum therapy for rabies), and the treatment effect is low when it occurs. In addition, interferon (IFN), a nonspecific bioresistance substance, is currently known as the most effective antiviral agent, but it is toxic to host cells, and produces fever, general malaise, headache, appetite. There is a problem that side effects such as poor performance, decreased white blood cell platelets, and central nervous system disorders are large.
さらに、抗ＲＮＡウイルス化学療法剤としてはリバビリン、アマンタジンが知られているが、その効果は低く、細胞毒性に伴う不眠、神経過敏等の副作用が強い。このため、ＲＮＡウイルス感染病に対して優れた抗ウイルス活性を有し、しかも、細胞、生体組織に対する副作用の少ない有効な治療薬の出現が待たれている状況にある。 Furthermore, ribavirin and amantadine are known as anti-RNA virus chemotherapeutic agents, but their effects are low and they have strong side effects such as insomnia and nervousness due to cytotoxicity. Therefore, there is a need for an effective therapeutic agent that has excellent antiviral activity against RNA virus infectious diseases and has few side effects on cells and living tissues.
そして、さらには、ＲＮＡウイルス感染病だけでなく、細菌感染に対しての防御性、つまり抗菌活性をも有し、広い範囲の感染病に対して有効な化学治療剤の出現が待たれてもいた。 Furthermore, there is a need for the development of chemotherapeutic agents that have not only RNA virus infectious diseases but also protection against bacterial infections, that is, antibacterial activity, and that are effective against a wide range of infectious diseases. Was.
このため、ＲＮＡウイルス感染病に対して優れた抗ウイルス活性を有し、しかも、細胞、生体組織に対する副作用の少ない有効な治療薬の出現が待たれている状況にある。 Therefore, there is a need for an effective therapeutic agent that has excellent antiviral activity against RNA virus infectious diseases and has few side effects on cells and living tissues.
そして、さらには、ＲＮＡウイルス感染病だけでなく、細菌感染に対しての防御性、つまり抗菌活性をも有し、広い範囲の感染病に対して有効な化学治療剤の出現が待たれてもいた。 Furthermore, there is a need for the development of chemotherapeutic agents that have not only RNA virus infectious diseases but also protection against bacterial infections, that is, antibacterial activity, and that are effective against a wide range of infectious diseases. Was.
この発明は、上記のとおりの課題を解決するものとして、次式 The present invention solves the problems as described above by the following formula:
（式中のＲ1は水素原子、メチル基、または１−ヒドロキシエチル基であり、Ｒ2およびＲ3は、水素原子またはヒドロキシル基である）
で表されるフラノナフトキノン誘導体を有効活性成分として含有することを特徴とする抗菌剤を提供する。
(Wherein R 1 is a hydrogen atom, a methyl group, or a 1-hydroxyethyl group, and R 2 and R 3 are a hydrogen atom or a hydroxyl group)
The antibacterial agent characterized by containing the furanonaphthoquinone derivative represented by these as an active ingredient.
この発明により、抗菌活性に優れ、しかも副作用の少ないフラノナフトキノン誘導体からなる抗菌剤が提供される。 According to the present invention, there is provided an antibacterial agent comprising a furanonaphthoquinone derivative having excellent antibacterial activity and having few side effects.
上記のとおりのフラノナフトキノン誘導体を有効活性成分とするこの発明の抗菌剤については、広範囲のフラノナフトキノン誘導体が用いられることになる。これらを例示すると、たとえば、２−メチルナフト〔２，３−ｂ〕フラン−４，９−ジオン、２−アセチルナフト〔２，３−ｂ〕フラン−４，９−ジオン、２−（１−ヒドロキシエチル）ナフト〔２，３−ｂ〕フラン−４，９−ジオン、ナフト〔２，３−ｂ〕フラン−４，９−ジオン、５（または８）−ヒドロキシ−２−（１−ヒドロキシエチル）ナフト〔２，３−ｂ〕フラン−４，９−ジオン、５（または８）−ヒドロキシナフト〔２，３−ｂ〕フラン−４，９−ジオン、２−メチル−５（または８）−ヒドロキシ−２−メチルナフト〔２，３−ｂ〕フラン−４，９−ジオン、１，３−ジメチルイソフラノナフトキノン、２−（アセチルエチレンアセタール）ナフト〔２，３−ｂ〕フラン−４，９−ジオン、８−ヒドロキシ−７−メトキシナフト〔２，３−ｂ〕フラン−４，９−ジオン、３−アセチル−５，８−ジメトキシ−２−メチルナフト〔２，３−ｂ〕フラン−４，９−ジオン等々が挙げられる。もちろん、これら例示に何ら限定されることなく、前記の式により表わされる様々な態様がこの発明には可能である。そして、前記式におけるアルキル基、ヒドロキシアルキル基、アルコキシアルキル基については、活性を阻害しない限り、他の任意の置換基、たとえばアルケニル基、シクロアルキル基、シクロアルケニル基、アリール基、ハロゲン原子、アミノ基、ニトロ基、シアノ基、チオール基、チオエーテル基、カルボキシル基、エステル基、アミド基、スルホニル基、ハロホルミル基、複素環基等々が結合されていてもよい。 A wide range of furanonaphthoquinone derivatives will be used for the antibacterial agent of the present invention using the furanonaphthoquinone derivative as an active ingredient as described above. When these are illustrated, for example, 2-methylnaphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4,9-dione, 2- (1-hydroxy Ethyl) naphtho [2,3-b] furan-4,9-dione, naphtho [2,3-b] furan-4,9-dione, 5 (or 8) -hydroxy-2- (1-hydroxyethyl) Naphtho [2,3-b] furan-4,9-dione, 5 (or 8) -hydroxynaphtho [2,3-b] furan-4,9-dione, 2-methyl-5 (or 8) -hydroxy -2-Methylnaphtho [2,3-b] furan-4,9-dione, 1,3-dimethylisofuranonaphthoquinone, 2- (acetylethyleneacetal) naphtho [2,3-b] furan-4,9-dione , 8-hydroxy-7-methoxy Shift [2,3-b] furan-4,9-dione, 3-acetyl-5,8-dimethoxy-2-methylnaphtho [2,3-b] furan-4,9-dione, etc. are exemplified. Of course, without being limited to these exemplifications, various embodiments represented by the above formulas are possible in the present invention. As for the alkyl group, hydroxyalkyl group and alkoxyalkyl group in the above formula, other arbitrary substituents such as alkenyl group, cycloalkyl group, cycloalkenyl group, aryl group, halogen atom, amino Groups, nitro groups, cyano groups, thiol groups, thioether groups, carboxyl groups, ester groups, amide groups, sulfonyl groups, haloformyl groups, heterocyclic groups and the like may be bonded.
これらの各種の化合物は、これまで公知の様々な化学的合成の手法、あるいは天然物としての樹皮等からのフラノナフトキノン類の抽出等によって製造することができる。 These various compounds can be produced by various known chemical synthesis techniques, or by extracting furanonaphthoquinones from bark or the like as a natural product.
そして、この発明の抗菌剤は、広い対象を有し、真菌類、グラム陰性菌等々について優れた抗菌作用を示す。 The antibacterial agent of the present invention has a wide range of objects, and exhibits excellent antibacterial activity against fungi, gram-negative bacteria, and the like.
このようなこの発明の抗菌剤は、液剤、固形剤等の様々な剤形において、経口、皮下、静脈、外用等の各種の方法によって処方することができる。当然、その際には、従来公知の配合成分を添加し、塩、エステル等の保護剤をはじめ各種の態様として薬剤組成を構成することができる。 Such an antibacterial agent of the present invention can be formulated in various dosage forms such as a liquid preparation and a solid preparation by various methods such as oral, subcutaneous, intravenous, and external use. Naturally, in that case, a conventionally well-known compounding component can be added, and a pharmaceutical composition can be constituted in various modes including a protective agent such as a salt and an ester.
そこで、以下、実施例を示し、この実施例に沿ってさらに詳しくこの発明について説明する。 Therefore, the present invention will be described below in more detail with reference to examples.
実施例１
（２−（１−ヒドロキシエチル）ナフト〔２，３−ｂ〕フラン−４，９−ジオンの製造）
ｓｅｃ−ＢｕＬｉを用いたメタレーション反応により合成した。すなわち、Ｎ，Ｎ−ジエチルベンズアミドに、エーテル中（又はＴＨＦ中）、−７８℃でｓｅｃ−ＢｕＬｉ（１ｅｑ．）とＴＭＥＤＡ（１ｅｑ．）を１時間反応させる。次に−７８℃で５−（１−ヒドロキシエチル）−３−フルアルデヒド誘導体（１ｅｑ．）を滴下し、さらにｓｅｃ−ＢｕＬｉ（４ｅｑ．）を加え徐々に室温にもどし、１晩攪拌を続ける。水を加えクロロホルム抽出し、クロロホルム層を飽和ＮａＣｌ水で洗った後、乾燥留去する。残渣をＰＴＬＣ（クロロホルム：アセトン＝１００：１）により分離精製し、保護基を除去し、次式の化合物の黄色結晶を得た。
Example 1
(Production of 2- (1-hydroxyethyl) naphtho [2,3-b] furan-4,9-dione)
It was synthesized by a metallation reaction using sec-BuLi. That is, sec-BuLi (1 eq.) And TMEDA (1 eq.) Are reacted with N, N-diethylbenzamide in ether (or in THF) at −78 ° C. for 1 hour. Next, a 5- (1-hydroxyethyl) -3-furaldehyde derivative (1 eq.) Is added dropwise at −78 ° C., sec-BuLi (4 eq.) Is further added, the temperature is gradually returned to room temperature, and stirring is continued overnight. After adding water and extracting with chloroform, the chloroform layer is washed with saturated NaCl water, and then dried and distilled off. The residue was separated and purified by PTLC (chloroform: acetone = 100: 1) to remove the protecting group, thereby obtaining a yellow crystal of the following compound.
実施例２
（２−メチルナフト〔２，３−ｂ〕フラン−４，９−ジオンの製造）
２−ヒドロキシ−１，４−ナフトキノンとプロピオンアルデヒドから合成した２−ヒドロキシ−３−（２−プロペニル）−１，４−ナフトキノン（１５０ｍｇ）とＤＤＱ（２００ｍｇ）をベンゼン（２０ｍｌ）中攪拌、還流する。２〜３時間後、冷却し、濾過して濾液を留去する。残渣をカラムクロマトグラフィー（シリカゲル３０ｇ、ベンゼン）にかけ、最初の黄色分画より目的の次式化合物を黄色結晶として得た（３５％）。
Example 2
(Production of 2-methylnaphtho [2,3-b] furan-4,9-dione)
2-Hydroxy-3- (2-propenyl) -1,4-naphthoquinone (150 mg) synthesized from 2-hydroxy-1,4-naphthoquinone and propionaldehyde and DDQ (200 mg) are stirred and refluxed in benzene (20 ml). . After 2-3 hours, cool, filter and evaporate the filtrate. The residue was subjected to column chromatography (silica gel 30 g, benzene) to obtain the target compound of the following formula as yellow crystals from the first yellow fraction (35%).
実施例３
（Ａ）８−ヒドロキシナフト〔２，３−ｂ〕フラン−４，９−ジオン、および（Ｂ）８−ヒドロキシ−２−メチルナフト〔２，３−ｂ〕フラン−４，９−ジオンの製造）
塩化アルミニウム（２．５ｇ）と無水３−ヒドロキシフタル酸（１ｇ）をニトロベンゼン（５ｍｌ）に加え、アセチルフラン（０．７ｇ）または２−アセチル−５−メチルフランを滴下し１００℃で一晩加熱する。その後、クロロホルム抽出しニトロベンゼンを減圧留去した後カラムクロマトグラフィー（シリカゲル５０ｇ、ベンゼン）にかけ、精製し、次式化合物の黄色結晶を得た（〜５％）。
Example 3
(A) Production of 8-hydroxynaphtho [2,3-b] furan-4,9-dione and (B) 8-hydroxy-2-methylnaphtho [2,3-b] furan-4,9-dione)
Aluminum chloride (2.5 g) and 3-hydroxyphthalic anhydride (1 g) were added to nitrobenzene (5 ml), acetylfuran (0.7 g) or 2-acetyl-5-methylfuran was added dropwise, and the mixture was heated at 100 ° C. overnight. I do. Thereafter, extraction with chloroform was performed, and nitrobenzene was distilled off under reduced pressure, and the residue was purified by column chromatography (50 g of silica gel, benzene) to obtain yellow crystals of the following compound (化合物 5%).
実施例４
（５−ヒドロキシ−２−（１−ヒドロキシエチル）ナフト〔２，３−ｂ〕フラン−４，９−ジオンの製造）
Tecomaipe 乾燥樹皮（ブラジル産）１０ｋｇを純メタノール１０ｌ宛で３０分３回加温還流下に抽出し、溶媒を減圧留去した。抽出物（１．４５ｋｇ）をクロロホルム４ｌ宛で３回冷浸し、クロロホルム層を水洗後、硫酸マグネシウムで乾燥し、溶媒を留去して抽出物１０ｇを得た。これをトルエン・酢酸エチルエステル（４：１）を展開溶媒としてシリカゲル６０Ｆ254 を用いて分離薄層クロマトグラフィーを反復して行い、Ｒｆ＝０．２４のスポットを抽出、クロロホルム−メタノール（９：１）で抽出し計８ｍｇの次式化合物を得た（融点１８１℃）。
Example 4
(Production of 5-hydroxy-2- (1-hydroxyethyl) naphtho [2,3-b] furan-4,9-dione)
Tecomaipe 10 kg of dried bark (produced in Brazil) was extracted three times for 30 minutes with 10 l of pure methanol under heating and reflux, and the solvent was distilled off under reduced pressure. The extract (1.45 kg) was cold-soaked three times with 4 l of chloroform, the chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 10 g of the extract. This was repeated by separation and thin-layer chromatography using silica gel 60F254 using toluene / acetic acid ethyl ester (4: 1) as a developing solvent to extract a spot with Rf = 0.24, chloroform-methanol (9: 1). To give a total of 8 mg of the following compound (melting point: 181 ° C.).
実施例５
（抗菌剤）
＜Ａ＞試験材料
白癬菌のTrichophyton rubrum とカンジダ真菌Candida albicansを用いた。
＜Ｂ＞試験方法
白癬菌の増殖阻止試験：サブローブドウ糖寒天培地に一定量の薬剤を加え、２５℃で７日間培養したとき、寒天培地表面に生じる白癬菌コロニー数を計測し、５０％成長阻止する薬剤濃度（ＬＤ50）を算定した。
Example 5
(Antibacterial agent)
<A> Test materials Trichophyton rubrum and Trichophyton rubrum, Candida albicans, were used.
<B> Test method Trichophyton growth inhibition test: When a certain amount of drug was added to Sabouraud glucose agar medium and cultured at 25 ° C. for 7 days, the number of Trichophyton colonies formed on the surface of the agar medium was counted to inhibit 50% growth. The drug concentration (LD50) was calculated.
カンジダ菌の増殖阻止試験：サブローブドウ糖ブイヨン培地に一定量の薬剤を加え、２５℃で５日間培養したとき、増殖する菌量を濁度法にて計測し、５０％成長阻止する薬剤濃度（ＬＤ50）を算定した。
＜Ｃ＞試験結果
前記実施例３Ｂと実施例４の化合物を用いた場合の結果を示したものが表７および表８である。
Inhibition test for growth of Candida: When a certain amount of drug is added to Sabouraud's glucose broth medium and cultured at 25 ° C for 5 days, the amount of the growing bacteria is measured by a turbidity method, and the concentration of the drug that inhibits 50% growth (LD50) ) Was calculated.
<C> Test Results Tables 7 and 8 show the results when the compounds of Example 3B and Example 4 were used.
この表７および表８に示したとおり、両化合物は、濃度依存性に白癬菌の増殖を阻止した。５０％増殖を阻止するＬＤ50値は、実施例４の化合物が０．０７０μｇ／ｍｌ、実施例３Ｂの化合物が０．８１μｇ／ｍｌと微量で有効であり、Candida 菌に対する実施例４の化合物のＬＤ50値４３μｇ／ｍｌ、実施例３Ｂの化合物の４９８μｇ／ｍｌに比べ、約６００倍白癬菌に対し強い抗菌作用を有している。 As shown in Tables 7 and 8, both compounds inhibited the growth of Trichophyton in a concentration-dependent manner. The LD50 value which inhibits 50% growth is as effective as 0.070 µg / ml for the compound of Example 4 and 0.81 µg / ml for the compound of Example 3B, and the LD50 value of the compound of Example 4 against Candida is effective. It has a strong antibacterial activity against Trichophyton about 600 times that of the compound of Example 3B at a value of 43 μg / ml, which is about 498 μg / ml of the compound of Example 3B.
以上のとおり、この発明のフラノナフトキノン誘導体は真菌に対し抗菌作用を示した。特に、この発明の化合物は、皮膚糸状真菌である白癬菌に対する抗菌作用に優れており、皮膚痒癬症に対する治療薬として有用であることがわかる。
実施例６
（抗菌剤）
＜Ａ＞試験材料
病原菌として、
ヘリコバクター・ピロリ Helicobacter pylori ＮＣＴＣ１１６３７（ヒト）
ヘリコバクター・フィリス Helicobacter feris（ネコ）
カンピロバクター・ジェジュニ Campylobacter jejuni
白癬菌Ｔ．メンタグロフィテス Trichophyton mentagrophytes
白癬菌Ｔ．ルブルム Trichophyton rubrum
を用いた。
As described above, the furanonaphthoquinone derivative of the present invention exhibited an antibacterial activity against fungi. In particular, the compound of the present invention has excellent antibacterial activity against Trichophyton dermatophytes, which is useful as a therapeutic agent for pruritus dermatitis.
Example 6
(Antibacterial agent)
<A> Test material
Helicobacter pylori NCTC 11637 (human)
Helicobacter feris (cat)
Campylobacter jejuni
Trichophyton T. Trichophyton mentagrophytes
Trichophyton T. Rubrum Trichophyton rubrum
Was used.
コントロールの常在菌として、
大腸菌 Escherichia coli
表層ブドウ球菌 Staphylococcus epidermis
カンジダ真菌 Candida albicans
を用いた。
＜Ｂ＞試験方法
馬血清５％を含むBrucella寒天培地に一定量の薬剤を加え、２４ウエルプレートに固めた後、１ウエル当たり約１０5 菌を接種した。ガスパック法で３７℃、２日間培養後、５５０ｎｍの吸光度によりコントロールに対する培殖率を測定し、菌の増殖を１００％抑制する薬剤の最小濃度ＭＩＣ（minimum inhibitory concentration）を算定した。
As a control resident bacterium,
Escherichia coli
Staphylococcus epidermis
Candida albicans
Was used.
<B> Test method A certain amount of drug was added to Brucella agar medium containing 5% of horse serum, and the mixture was solidified in a 24-well plate, and then about 10 5 bacteria were inoculated per well. After culturing at 37 ° C. for 2 days by the gas pack method, the cultivation rate with respect to the control was measured by absorbance at 550 nm, and the minimum concentration MIC (minimum inhibitory concentration) of the drug which inhibits bacterial growth by 100% was calculated.
実施例２、実施例４、そして実施例３Ａ、３Ｂの化合物を用いた結果を示したものが表９である。 Table 9 shows the results obtained using the compounds of Examples 2, 4, and 3A and 3B.
この表９に示したとおり、実施例２および実施例３Ａ、３Ｂの化合物は、極低濃度（０．０３５〜０．０７μｇ／ｍｌ）でヘリコバクターの増殖を完全に抑制し、０．６３〜１．２５μｇ／ｍｌでカンピロバクターの増殖を完全に抑制した。また、実施例２および実施例３Ａ、３Ｂの化合物は、６．２５μｇ／ｍｌで白癬菌の増殖を完全に抑制し、実施例４の化合物は０．５μｇ／ｍｌで増殖を完全に抑制した。 As shown in Table 9, the compounds of Example 2 and Examples 3A and 3B completely inhibited the growth of Helicobacter at extremely low concentrations (0.035 to 0.07 μg / ml), and showed the compound of 0.63 to 1 At 0.25 μg / ml, the growth of Campylobacter was completely inhibited. The compounds of Example 2 and Examples 3A and 3B completely inhibited the growth of Trichophyton at 6.25 μg / ml, and the compound of Example 4 completely inhibited the growth at 0.5 μg / ml.
コントロールの大腸菌、表層ブドウ球菌の増殖を完全に抑制するには実施例２および実施例３Ｂの化合物とも２５〜１００μｇ／ｍｌを要した。 To completely suppress the growth of the control E. coli and Staphylococcus aureus, the compounds of Examples 2 and 3B each required 25 to 100 μg / ml.
以上の結果から、この発明のフラノナフトキノン誘導体はヘリコバクター、カンピロバクター、白癬菌に対し強い選択的抗菌作用を有すること明らかになった。 From the above results, it was revealed that the furanonaphthoquinone derivative of the present invention has a strong selective antibacterial action against Helicobacter, Campylobacter and Trichophyton.
カンピロバクターは腸炎の原因菌であり、ヘリコバクターは最近胃炎、胃潰瘍、十二指腸潰瘍、胃癌の原因菌としての可能性が指摘されており、白癬菌は水虫の原因菌でありこれら疾患の予防治療の両面からフラノナフトキノン誘導体の抗菌作用は重要である。 Campylobacter is the causative agent of enteritis, and Helicobacter is recently pointed out as a causative agent of gastritis, stomach ulcer, duodenal ulcer, and gastric cancer.Trichophyton is a causative agent of athlete's foot and both preventive and therapeutic treatments for these diseases The antibacterial activity of furanonaphthoquinone derivatives is important.
胃液には数ｍＭの尿素が含まれており胃や十二指腸内の生理的環境の保全に役立っているが、ヘリコバクターが胃に感染すると、この菌がもつ強いウレアーゼ活性が尿素を分解しアンモニアを生成することで菌周囲の胃酸を中和し、そこに定着する。その結果、定着したヘリコバクターが生成するアンモニアが胃や十二指腸粘膜を障害して潰瘍や胃癌の発生原因を作るとともに、血中アンモニア濃度が高まり、肝障害患者においてはその障害を助長する。現在プロトンポンプ阻害剤オメプラゾール、ランソプラゾールなどがヘリコバクター感染の胃炎、胃潰瘍、カンピロバクター腸炎の除菌治療薬として用いられているが、それらのＭＩＣは数μｇ／ｍｌと高く、副作用（じんま疹、肝障害、下痢、便秘、悪心、嘔吐、頭痛、胎児毒性等）があるが、この発明の場合にはこのような心配は顕著に軽減される。 Gastric juice contains several mM urea, which helps to preserve the physiological environment in the stomach and duodenum.However, when Helicobacter infects the stomach, the strong urease activity of this bacterium degrades urea to produce ammonia. By doing so, the stomach acid around the bacteria is neutralized and settled there. As a result, the ammonia generated by the established Helicobacter damages the stomach and duodenal mucosa and causes ulcers and gastric cancer, and also increases the blood ammonia concentration, which promotes the disorder in patients with liver injury. Currently, proton pump inhibitors such as omeprazole and lansoprazole are used as antibacterial treatments for gastritis, gastric ulcer, and Campylobacter enteritis caused by Helicobacter infection, but their MIC is as high as several μg / ml and their side effects (urticaria, liver damage) , Diarrhea, constipation, nausea, vomiting, headache, fetal toxicity, etc.), but in the case of the present invention, such concerns are remarkably reduced.
実際、この発明のフラノナフトキノン誘導体の培養ヒト正常細胞の増殖を完全に抑制する濃度は２０〜５０μｇ／ｍｌであって、ヘリコバクター、カンピロバクター、白癬菌に比べ約２０分の１〜１００分の１と低い。このため、細胞毒性の低いフラノナフトキノン誘導体の有用性が期待される。 In fact, the concentration of the furanonaphthoquinone derivative of the present invention that completely suppresses the growth of cultured normal human cells is 20 to 50 μg / ml, which is about 1/100 to 1/100 of that of Helicobacter, Campylobacter and Trichophyton. Low. Therefore, the usefulness of the furanonaphthoquinone derivative having low cytotoxicity is expected.
Claims (1)
で表されるフラノナフトキノン誘導体を有効活性成分として含有することを特徴とする抗菌剤。 Next formula
An antibacterial agent comprising the furanonaphthoquinone derivative represented by the formula (1) as an active ingredient.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7538234B2 (en) | 2007-05-31 | 2009-05-26 | Taheebo Japan Co., Ltd. | Preparation of Optically active 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4, 9-diones having anticancer activities |
| US7910752B2 (en) | 2005-03-16 | 2011-03-22 | Taheebo Japan Co., Ltd. | Anticancer compound, intermediate therefor, and processes for producing these |
| US9730909B2 (en) | 2010-03-19 | 2017-08-15 | Boston Biomedical, Inc | Methods for targeting cancer stem cells |
| US9732055B2 (en) * | 2007-09-10 | 2017-08-15 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US10543189B2 (en) | 2013-04-09 | 2020-01-28 | Boston Biomedical, Inc. | 2-acetylnaphtho[2,3-b]furan -4,9-dione for use on treating cancer |
| US10646464B2 (en) | 2017-05-17 | 2020-05-12 | Boston Biomedical, Inc. | Methods for treating cancer |
| US11299469B2 (en) | 2016-11-29 | 2022-04-12 | Sumitomo Dainippon Pharma Oncology, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
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2004
- 2004-04-21 JP JP2004124961A patent/JP2004224802A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7910752B2 (en) | 2005-03-16 | 2011-03-22 | Taheebo Japan Co., Ltd. | Anticancer compound, intermediate therefor, and processes for producing these |
| US7538234B2 (en) | 2007-05-31 | 2009-05-26 | Taheebo Japan Co., Ltd. | Preparation of Optically active 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4, 9-diones having anticancer activities |
| US9732055B2 (en) * | 2007-09-10 | 2017-08-15 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US9745278B2 (en) | 2007-09-10 | 2017-08-29 | Boston Biomedical, Inc. | Group of STAT3 pathway inhibitors and cancer stem cell pathway inhibitors |
| US10377731B2 (en) | 2007-09-10 | 2019-08-13 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US10851075B2 (en) | 2007-09-10 | 2020-12-01 | Sumitomo Dainippon Pharma Oncology, Inc. | Stat3 pathway inhibitors and cancer stem cell inhibitors |
| US9730909B2 (en) | 2010-03-19 | 2017-08-15 | Boston Biomedical, Inc | Methods for targeting cancer stem cells |
| US10543189B2 (en) | 2013-04-09 | 2020-01-28 | Boston Biomedical, Inc. | 2-acetylnaphtho[2,3-b]furan -4,9-dione for use on treating cancer |
| US11299469B2 (en) | 2016-11-29 | 2022-04-12 | Sumitomo Dainippon Pharma Oncology, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
| US10646464B2 (en) | 2017-05-17 | 2020-05-12 | Boston Biomedical, Inc. | Methods for treating cancer |
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